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Value and limitations of myocardial thallium washout rate in the noninvasive diagnosis of patients with triple-vessel coronary artery disease
Value and limitations of myocardial tha#lium washout rate in the noninvasive diagnosis of patients with triple-vessel coronary artery disease This study tested the hypothesis that recognition of delayed washout of thallium from myocardial scan zones with apparently normal thallium uptake is useful for identifying patients with triple-vessel coronary artery disease (CAD). Exercise thallium stress tests were performed in 21 patients with angiographically proven triple-vessel CAD (?50% stenosis of all three major vessels). Anterior and left anterior oblique thallium images were obtained 5 to 10 minutes after stress and 2 hours later. Background corrected scans (bilinear interpolative method) were analyzed by computer (radial analysis program) for the presence of Initial uptake defects as well as delayed thallium washout. Twenty-five patients with single or double-vessel CAD and 14 patients with normal coronary arteries also were studied to obtain specificity data regarding the diagnosis of triple-vessel coronary disease. In patients with triple-vessel CAD, 50 of 63 (79%) stenosed vessels were detected by combined use of uptake and washout criteria. However, only 8 of 63 (13%) diseased vessels were detected by washout criteria alone. Nevertheless, use of washout criteria did increase the number of patients correctly identified as having triple-vessel disease from seven (identified on the basis of uptake defects alone) to 10. Accordingly, sensitivity using both uptake and washout criteria was 48% (10 of 21 patients). Specificity for the diagnosis of triple-vessel disease using combined uptake and washout criteria was 76% for patients with single- or double-vessel CAD and 95% for normals, and was little different from values obtained based on uptake criteria alone (80% and lOO%, respectively). Thus even though relatively few stenosed vessels in patients with triple-vessel CAD are associated with isolated thallium washout abnormalities, use of washout criteria does increase the sensitivity of the thallium stress test for the detection of such patients and therefore is a worthwhile addition to routine uptake analysis of thallium images of the myocardium. (AM HEART J 106:681, 1983.)
Henry Gewirtz, M.D., Walter Paladino, Albert S. Most, M.D. Providence, R.I.
M.D., Michael
Sullivan,
M.S.E.E.,
and
Previous studies in laboratory animals have shown that myocardial segments rendered ischemic prior to thallium administration exhibit reduced initial tracer uptake and delayed washout of isotope in comparison with myocardial segments having normal perfusion at the time of thallium administration.’ Since myocardial thallium scans obtained immediately after exercise stress testing demonstrate relative but not absolute levels of myocardial blood flow, it is possible that myocardial segments with apparently normal initial tracer uptake may nevertheless have abnormal perfusion. Furthermore, under conditions
of uniform global myocardial ischemia, initial perfusion defects on thallium images may be absent altogether.le3 In light of these considerations, other investigators2v3 have recently proposed that quantitative computer analysis of myocardial thallium washout rates may be useful for detecting scan segments with apparently normal initial tracer uptake but delayed tracer washout and hence what might be termed occult ischemia. Recognition of such segments could help to improve the ability of thallium stress testing to identify patients with triple-vessel coronary artery disease. The following study was performed in order to test this hypothesis.
From the Department Hospital; and Brown
METHODS
Received Reprint Hospital,
for publication
of Medicine, Cardiology Section, University, Program in Medicine. March
requests: Henry Gewirtz, Providence, RI 02902.
17, 1982; M.D.,
accepted Cardiology
Apr.
Rhode
Island
26, 1982.
Section,
Rhode
Island
Patient population. Three groups of patients were studied. Group I consisted of 21 patients with angiographically proven triple-vessel coronary artery disease (~50% 681
682
Gewirtz
et al.
American
October. 1983 Heart Journal
1. The panel on the left shows an anterior thallium scan from one of the patients (M.B.) participating in the study. The image on the right is the same as that on the left and shows the computer-identified myocardial pixels with maximal counts at each 6 degreesof arc. The white arrow indicates the left ventricular apex (designatedzero degrees).Radii are numbered proceedingcounterclockwisefrom the apex. Thus 90 degreesis located roughly at the mid anterolateral wall in this view. The panel on the right showsthe results of thallium uptake analysisfor the imageon the left. The curve describing the lower limits of normal tracer uptake at each radial location is indicated by plus (+) symbols. The patient’s uptake curve is indicated by diamond (0) symbols. Note that an uptake defect is present from approximately 225 to 355 degrees.This correspondsto the region of obviously diminished tracer uptake along the inferior wall (with extension into the apex). Fig.
reduction in luminal diameter of all three major coronary arteries). All patients were males, mean age 53 years (range 34 to 72 years). ECG evidence of prior myocardial infarction was present in 11 patients (10 infarcts inferior or posterior in location, one anterior). Eleven patients were taking propranolol at the time of the imaging study. The mean interval between the time of cardiac catheterization and the imaging study was 3 months (range 1 day to 12 months). Delay between studiesreflected the limited number of appointments available for thallium stresstests at our institution and the relative ease in scheduling cardiac catheterization. All patients included in the study remained clinically stable between investigations. Group II wascomposedof 25 patients with angiographically proven single- or double-vessel coronary artery disease.Mean age of these patients was 52 years (range 33 to 68 years). There were 22 males and 3 females in this group. ECG evidence of previous myocardial infarction was present in seven patients (three infarcts inferior/ posterior in location and four anterior). At the time of the imaging study 17 patients were taking propranolol. The mean interval between the time of cardiac catheterization and the imaging study was 1 month (range 1 day to 10 months) in this group of patients. Fourteen patients with angiographically normal coronary arteries comprised group III. Mean age of these patients was 49 years (range 39 to 61 years). There were nine malesand five females in the group. All underwent cardiac catheterization for evaluation of atypical chest pain. None of these patients had ECG evidence of prior myocardial infarction. Five of the patients were taking propranolol at the time of the imaging study. Stress test protocol. All patients underwent a clinically indicated, symptom-limited, maximal exercise stress test. The test was ordered at the behest of the patient’s
personal physician. Written informed consent was obtained for the procedure from each patient. Prior to the study a resting 12-lead ECG was obtained along with a brief physical examination of the cardiovascular system. Exercise was performed on an upright bicycle ergometer (Warren E. Collins, Waltham, Mass.). The patients pedaled the bicycle at a constant rate beginning with a workload of 150 kpm and increasing by 150 kpm every 3 minutes. Blood pressure (cuff) and a 12-lead ECG was recorded at 2.5 minutes into each workload. The test was terminated if any of the following end points was achieved: (1) exhaustion, (2) typical angina pectoris with 24 mm horizontal ST segmentdepressionat 80 msecafter the J point, and (3) any other contraindication to continuing stress(e.g., onset of ventricular tachycardia, hypotension, left bundle branch block). A positive ECG response to stresswas defined as ~1 mm horizontal ST segment depressionat 80 msecafter the J point. Acquisition and analysis of thallium images. One minute prior to discontinuing stress the patient was injected intravenously with 2.0 mCi of thallium-201. Exercise was continued for an additional minute, after which the patient was positioned in front of a gamma camera (Ohio Nuclear, Series420) located in the sameroom asthe bicycle ergometer. The camera was equipped with a general all-purpose collimator and was interfaced to a Medical Data Systems computer system (MDS, Ann Arbor, Mich.). Imageswere obtained for 300K counts in a 128 X 128matrix in the anterior and 45-degreeleft anterior oblique projections beginning at 7 minutes and 2 hours after tracer administration. Acquisition time for each scan was carefully noted. Images were processed by one observer who was unaware of either exercise or angiographic data for the patient. The following procedure wasemployed. First, the
Volume Number
106 4. Part 1
Myocardial
128 x 128imageswere zoomed into a 64 x 64 word matrix encompassingonly the myocardium and the region immediately surrounding it. Next, a commercially available 9 point smoothing algorithm was used to smooth the zoomed images. After this the image was background corrected by means of a modified bilinear interpolative technique previously described by others.4The computer then located the pixel with maximal myocardial counts along radii drawn at each 6 degreesof arc from the center of the image (Fig. 1). Each pixel so identified was flagged by the computer and wasverified by the operator to insure that only pixels within the myocardium were analyzed. The computer then generated an uptake curve for each image. The curve consistedof the actual count values for each of the identified pixels with maximal myocardial uptake at each 6 degreesof arc. To determine if an initial uptake defect was present, each point on the curve was normalized to the point with maximal counts. The uptake curve wasthen compared againsta template derived from 14 normal patients. A defect was said to occur if two or more adjacent radii had normalized uptake values more than 2 standard deviations below the mean for normals (Fig. 1). In order to determine thallium washout at each radial location within the myocardium, uptake curves for initial and late imageswere divided by the appropriate acquisition time for each scan. The count rate at each radial location of the late (i.e., 2 hour) curve wasthen subtracted from the count rate of the corresponding point on the early curve, the result wasdivided by the count rate value for each point along the early curve and was then multiplied by 100 in order to obtain percent washout at each radial location. The resulting percent washout curve for anterior and left anterior oblique (LAO) views was compared against appropriate washout templates derived from the previously mentioned 14 normal patients. If two or more adjacent radii were more than 2 standard deviations below the mean for normal patients, delayed thallium washoutwassaid to be present. It should be noted that the method usedto assessuptake and washout abnormalities is essentially the sameas that described by Maddahi et a1.2 The intra- and interobserver variability of this method for analyzing the thallium imageswasassessed in a subset of 11 patients chosen at random from the larger study population. Intraobserver variability wasassessed by having one observer processall imagesa secondtime approximately 4 months after initial processinghad been completed. The results of uptake and washout analysis were compared on a segment-by-segmentbasis.Interobserver variability wasassessed by comparing the resultsobtained for uptake and washout analysis in 11 patients by 2 independent observers. For the purposesof assessing the presenceor absenceof triple-vessel coronary artery disease, defects of either uptake or washout along the anterior wall and septum were assignedto the left anterior descending coronary artery. Defects involving the inferior wall in the anterior view were assignedto the right coronary artery or left
Tl-201
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rate and triple-vessel
CAD
663
circumflex if the left circumflex was a dominant system. Defects alongthe posterolateral wall in the LAO view were assignedto the circumflex coronary artery. Apical defects in the LAO view were not considered specific for any coronary vessel. Defects in the apical segment of the anterior view were assignedto the coronary vesselsupplying the apex of the left ventricle. It should be noted that the apex in both anterior and LAO views was identified by the operator and arbitrarily designatedaszero degrees.Radii were numbered proceeding counterclockwise from the apex. Accordingly, in the anterior view (Fig. 1) the apical segment extended between336 and 30 degrees,the anterior segmentextended from 36 to 130 degrees, and the inferior segment extended from 240 to 330 degrees.In the LAO view the apex extended between 336and 24 degrees,the posterolatera1segment extended between 30 and 126 degrees,and the septum extended from 246 to 330 degrees. Statistics. Sensitivity for detection of triple-vessel coronary diseasewas defined as the number of true positive tests divided by true positive plus false negative tests. Specificity was defined as true negative tests divided by true negative plus false positive tests. For the purposesof this study a true negative test was defined as a test in which a patient without triple-vessel diseasewasclassified as belonging to any category other than triple-vessel coronary artery disease.A true positive test wasdefined as a test in which a patient with triple-vessel coronary artery diseasewasassignedto the triple-vessel category. In order to evaluate the post test predictive value of thallium imaging for detecting patients with triple-vessel coronary disease,Baysian analysis of the data also wasperformed.5 Finally, it should be noted that specificity of the imaging test was evaluated in patients with normal coronary arteries by testing each patient’s uptake and washout curves against an appropriate normal template derived from the other 13 patients. This “jacknife” procedure permitted us to assessspecificity in normal patients without having to assemblea second group of normal individuals for testing against the original normal templates. RESULTS Exercise stress testing. In the triple-vessel disease group (n = 21 patients), 10 patients experienced typical angina pectoris during the test. ST segment depression greater than 1 mm was observed in 13 patients. The mean duration of exercise was 602 + 213 (SD) seconds. Mean rate-pressure product (heart rate X systolic arterial pressure) at peak stress was 19,005 r+ 6057 mm Hg . min-‘. Four patients obtained target heart rate. In the patients with single- or double-vessel coronary disease (n = 25 patients), 11 experienced typical angina pectoris during the test. Fourteen exhibited ST segment depression greater than 1 mm. Mean exercise duration in this group was 641 it 207 seconds.
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Gewirtz et al.
American
2. Shown here are the results of Baysian analysis of the imaging data. The curve depicted by closed circles (0) describes the post test probability of triple-vessel coronary artery disease (CAD) as a function of prevalence of triple-vessel CAD in a given population given a positive imaging test. The curve depicted by open circles ( 0) shows the post test probability of CAD given a negative imaging test. The difference between the two curves is shown by the triangles. The maxima of the difference function
Fig.
defines the diseaseprevalence (i.e., 40%)
at which the
imaging test best separates triple-vessel CAD patients from all other groups. The thin broken line is the line of identity. .
Mean rate-pressure product at peak stress was 19,844 +- 5394 mm Hg . min-‘. Only three patients obtained target heart rate in this group. Imaging results. In the group of patients with triple-vessel coronary artery disease, 30 of 63 vessels (48%) were associated with scan segments having both uptake and washout abnormalities. An additional 12 of 63 (19% ) diseased vessels were associated with isolated uptake defects on the thallium scan, while only 8 of 63 (13 % ) were associated with an isolated washout abnormality. Thus a relatively small percentage of all stenosed vessels were detected by delayed thallium washout alone. Nevertheless, use of combined uptake and washout criteria permitted 50 of 63 (79%) stenosed vessels to be detected. Analysis of the data on a patient-by-patient basis in the triple-vessel disease group demonstrated that 7 of 21 patients (33%) were correctly classified as having triple-vessel disease based on the presence of uptake abnormalities alone. The use of washout criteria enabled three additional patients to be recognized as having triple-vessel disease and
1983
Heart Journal
increased the percentage of patients correctly classified to 48%. In order to assess the specificity of quantitative computer analysis of thallium images for the detection of patients with triple-vessel coronary disease, we evaluated this methodology in the group of patients with single- or double-vessel coronary artery disease and in the group with angiographically normal coronary arteries. Eighty percent of patients with single- or double-vessel disease were true negative based on uptake criteria alone, while 100% of the normal patients were appropriately classified as true negative. When washout criteria were used in conjunction with uptake criteria, the percent of patients classified as true negative for triple-vessel disease declined slightly in each group: to 76% in the single- or double-vessel group and to 95% in the normal group. Accordingly, the data indicate that addition of washout to uptake criteria does not substantially reduce the specificity of the test for the diagnosis of triple-vessel coronary artery disease. Fig. 2 illustrates the results of Baysian analysis of the data. The specificity of the imaging test was found to be 76% in patients with single/doublevessel disease and 95% in normals. Since 25 of 39 (64 % ) patients without triple-vessel disease had single- or double-vessel coronary artery disease, a weighted mean value of 80% was taken as the best estimate of the true specificity of the imaging test. The sensitivity of the test was observed to be 48% but was rounded off to 50% for ease of analysis. The figure shows the post test probability of triple-vessel coronary disease as a function of the prevalence of triple-vessel disease in a given population. The curve described by the solid circles illustrates the post test probability of triple-vessel disease given a positive imaging test, while the curve described by the open circles indicates the post test probability of triple-vessel disease given a negative imaging test. The triangles represent the difference between the two curves. The point at which the difference function reaches a maximum (i.e., 40%) indicates the disease prevalence at which the test best separates patients with triple-vessel disease from all other
groups. It is apparent from the graph that with disease prevalence in the range of 30% to 50%) a negative test reduces the post test likelihood of triple-vessel disease only modestly. However, a positive test increases the post test probability of disease at least moderately (i.e., from 40% to 63%). Finally, the interobserver agreement for recogni-
Volume Number
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Myocardial
tion of scan segments with abnormal uptake was 77 % (51 of 66 scan segments), while the interobserver agreement for recognition of scan segments with abnormal washout was 80% (53 of 66 scan segments). Intraobserver agreement was found to be 79% (52 of 66 scan segments) for recognition of scan segments with abnormal uptake and 80% for recognition of scan segments with abnormal thallium washout. DISCUSSION
The principal objective of this study was to determine if quantitative computer analysis of myocardial thallium washout rates would be helpful in improving the ability of the thallium stress test to detect patients with triple-vessel coronary artery disease. In light of recent data6*7 which indicate that such patients not only achieve improved symptomatic relief but also may live longer as a result of coronary artery bypass surgery, a noninvasive method for recognition of patients with triple-vessel coronary disease would be of considerable value. Although previous investigators2g3 have emphasized that quantitative computer analysis of thallium scans, including analysis of segmental thallium washout rates, increases the recognition of diseased coronary arteries and improves the recognition of patients with multivessel coronary disease, it has not been shown that such methods of image analysis are useful in specifically recognizing the patient with triple-vessel coronary artery disease. Accordingly, the present investigation was undertaken in order to test the hypothesis that use of washout in addition to uptake criteria for recognition of defects in thallium images of the myocardium would aid in the noninvasive detection of patients with triple-vessel coronary artery disease. Improved sensitivity. The results of this investigation demonstrate that estimation of myocardial thallium washout rates does increase the sensitivity of the imaging test for recognition of patients with triple-vessel coronary artery disease. Further, although the gain in sensitivity is moderate, specificity is reduced very little by use of washout criteria. Therefore in light of the potential importance of recognizing patients with triple-vessel coronary disease, it would appear worthwhile to determine thallium washout rates in all patients undergoing thallium stress testing. Although a negative imaging test for triple-vessel disease does not exclude the diagnosis, a positive test enhances the post test probability that triple-vessel disease is present in a given patient.
Tl-201
washout
rate and triple-vessel
CAD
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The reasons why the thallium stress test was not more sensitive in recognizing triple-vessel disease in patients is probably related to several factors. First, it must be recalled that thallium imaging provides physiologic information concerning myocardial perfusion and cell viability. In contrast, the coronary arteriogram provides anatomic information about the coronary circulation. Accordingly, because a vessel’s luminal diameter has been reduced 50% or more than 50% does not necessarily mean that it will cause myocardial ischemia during a stress test. Other more severely stenosed vessels may cause the patient to experience angina and/or even transient heart failure and so may limit the patient’s ability to exercise before other less severely stenosed vessels can cause myocardial ischemia. Second, we (present study) as well as others2s8 have observed that the range of myocardial thallium uptake and washout in normal patients is a fairly broad one. Accordingly, some marginally but abnormally perfused myocardial segments may show uptake or washout which nevertheless falls within 2 standard deviations of the mean of normals. Third, it must be recalled that the planar thallium image is a two-dimensional representation of a three-dimensional object. Accordingly, scan segments are not always seen in isolation and therefore overlap of normal and abnormal segments may in some cases prevent recognition of either uptake or washout abnormalities. Fourth, it has also been proposed by others9 that evaluation of the ST segment response to stress may, in conjunction with the results of thallium imaging, improve recognition of patients with triple-vessel disease. However, in our study all six patients with a markedly positive stress test (defined as L to 3 mm horizontal ST segment depression at a workload of 1450 kpm [equivalent to stage I of a standard Bruce protocol]) and triple-vessel coronary disease were correctly classified as true positive on the basis of thallium imaging alone. Thus addition of the ECG response to stress would not have improved the recognition of triple-vessel disease in our patients. Finally, it should be pointed out that the rate of detection of stenosed vessels in our patients with triple-vessel disease (‘79 % ) was comparable to the rate (83 % ) achieved by Maddahi et al2 in their patients with triple-vessel disease. Propranotol. The role of propranolol in influencing the results of the study should also be considered. It has been proposed that propranolol may contribute to false positive imaging tests by blunting the patient’s exercise response to stress, hence causing delayed thallium washout in normal myocardial
October,
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segment. However, in our study specificity was high (76% in one- and two-vessel patients and 95% in normal patients). Moreover, others have shown that presence of propranolol generally does not cause false positive imaging tests as assessed by thallium washout criteria.2s3 We also observed in the triplevessel disease group that 6 of 11 patients with true positive imaging tests were taking propranolol, in comparison with 5 of 10 patients with false negative tests. Hence propranolol also did not appear to influence the results in terms of altering the incidence of true positive or false negative tests in the triple-vessel disease group. Conclusion. A computer based method for assessing washout of thallium from the myocardium offers an increase in sensitivity for detection of patients with triple-vessel coronary artery disease in comparison with assessment of initial perfusion defects alone. Given an incidence of triple-vessel disease of roughly 30% to 40% in a population, computer analysis of images using combined uptake and washout criteria is capable of increasing the post test probability of triple-vessel disease from 30% to 40 % to a range of 60% to 65%. Thus in view of the relative ease of analysis and potential importance in recognizing such patients (particularly in light of recent studies which indicate that these individuals may benefit from coronary artery bypass surgery), it is worthwhile to assess thallium washout rates in patients undergoing thallium stress testing.
American
Heart
1983 Journal
The authors express their appreciation to Christine Abatiello and Katherine Seropian for help in the preparation of the manuscript. REFERENCES
1. Beller GA, Watson DD, Ackell P, Pohost GM: Time course of thallium-201 redistribution after transient myocardial ischemia. Circulation 61:791, 1980. 2. Maddahi J, Garcia EV, Berman DS, Waxman A, Swan HJC, Forrester J: Improved noninvasive assessment of coronary artery disease by quantitative analysis of regional stress myocardial distribution and washout of thallium-201. Circulation 64:924, 1981. 3. Berger BC, Watson DD, Taylor GJ, Craddock GB, Martin RP, Teates CD, Beller GA: Quantitative thallium-201 exercise scintigraphy for detection of coronary artery disease. J Nucl Med 22:585, 1981. 4. Watson DD, Campbell NP, Reak EK, Gibson RS, Teates CD, Beller GA: Spatial and temporal quantitation of plane thallium myocardial images. J Nucl Med 22:577, 1981. 5. Hamilton GW, Trobaugh GB, Ritchie JL, Gould KL, DeRoven TA, Williams DL: Myocardial imaging with thallium-201: An analysis of clinical usefulness based on Bayes’ theorem. Scemin Nucl Med 6:358, 1978. SH: Coronary bypass surgery for chronic angi6. Rahimtoola na-1981. A perspective. Circulation 66225, 1982. 7. European Coronary Surgery Study Group: Coronary artery bypass surgery in stable angina pectoris: Survival at two years. Lancet 1:889, 1979. 8. Becker LC, Rogers WJ, Edwards AC: Limitations of thallium “washout rate” measurements after exercise for detection of coronary artery stenosis (abstr). Circulation 62(suppl III):III231, 1981. J, Barbour D, Garcia EV, Swan HJC, 9. Abdulla A, Maddahu Berman DS: Noninvasive identification of left main and triple vessel coronary artery disease in patients with prior myocardial infarction (abstr). Circulation 64(suppl IV):IV184, 1981.
Henry Gewirtz, M.D., Walter Paladino, Albert S. Most, M.D. Providence, R.I.
M.D., Michael
Sullivan,
M.S.E.E.,
and
Previous studies in laboratory animals have shown that myocardial segments rendered ischemic prior to thallium administration exhibit reduced initial tracer uptake and delayed washout of isotope in comparison with myocardial segments having normal perfusion at the time of thallium administration.’ Since myocardial thallium scans obtained immediately after exercise stress testing demonstrate relative but not absolute levels of myocardial blood flow, it is possible that myocardial segments with apparently normal initial tracer uptake may nevertheless have abnormal perfusion. Furthermore, under conditions
of uniform global myocardial ischemia, initial perfusion defects on thallium images may be absent altogether.le3 In light of these considerations, other investigators2v3 have recently proposed that quantitative computer analysis of myocardial thallium washout rates may be useful for detecting scan segments with apparently normal initial tracer uptake but delayed tracer washout and hence what might be termed occult ischemia. Recognition of such segments could help to improve the ability of thallium stress testing to identify patients with triple-vessel coronary artery disease. The following study was performed in order to test this hypothesis.
From the Department Hospital; and Brown
METHODS
Received Reprint Hospital,
for publication
of Medicine, Cardiology Section, University, Program in Medicine. March
requests: Henry Gewirtz, Providence, RI 02902.
17, 1982; M.D.,
accepted Cardiology
Apr.
Rhode
Island
26, 1982.
Section,
Rhode
Island
Patient population. Three groups of patients were studied. Group I consisted of 21 patients with angiographically proven triple-vessel coronary artery disease (~50% 681
682
Gewirtz
et al.
American
October. 1983 Heart Journal
1. The panel on the left shows an anterior thallium scan from one of the patients (M.B.) participating in the study. The image on the right is the same as that on the left and shows the computer-identified myocardial pixels with maximal counts at each 6 degreesof arc. The white arrow indicates the left ventricular apex (designatedzero degrees).Radii are numbered proceedingcounterclockwisefrom the apex. Thus 90 degreesis located roughly at the mid anterolateral wall in this view. The panel on the right showsthe results of thallium uptake analysisfor the imageon the left. The curve describing the lower limits of normal tracer uptake at each radial location is indicated by plus (+) symbols. The patient’s uptake curve is indicated by diamond (0) symbols. Note that an uptake defect is present from approximately 225 to 355 degrees.This correspondsto the region of obviously diminished tracer uptake along the inferior wall (with extension into the apex). Fig.
reduction in luminal diameter of all three major coronary arteries). All patients were males, mean age 53 years (range 34 to 72 years). ECG evidence of prior myocardial infarction was present in 11 patients (10 infarcts inferior or posterior in location, one anterior). Eleven patients were taking propranolol at the time of the imaging study. The mean interval between the time of cardiac catheterization and the imaging study was 3 months (range 1 day to 12 months). Delay between studiesreflected the limited number of appointments available for thallium stresstests at our institution and the relative ease in scheduling cardiac catheterization. All patients included in the study remained clinically stable between investigations. Group II wascomposedof 25 patients with angiographically proven single- or double-vessel coronary artery disease.Mean age of these patients was 52 years (range 33 to 68 years). There were 22 males and 3 females in this group. ECG evidence of previous myocardial infarction was present in seven patients (three infarcts inferior/ posterior in location and four anterior). At the time of the imaging study 17 patients were taking propranolol. The mean interval between the time of cardiac catheterization and the imaging study was 1 month (range 1 day to 10 months) in this group of patients. Fourteen patients with angiographically normal coronary arteries comprised group III. Mean age of these patients was 49 years (range 39 to 61 years). There were nine malesand five females in the group. All underwent cardiac catheterization for evaluation of atypical chest pain. None of these patients had ECG evidence of prior myocardial infarction. Five of the patients were taking propranolol at the time of the imaging study. Stress test protocol. All patients underwent a clinically indicated, symptom-limited, maximal exercise stress test. The test was ordered at the behest of the patient’s
personal physician. Written informed consent was obtained for the procedure from each patient. Prior to the study a resting 12-lead ECG was obtained along with a brief physical examination of the cardiovascular system. Exercise was performed on an upright bicycle ergometer (Warren E. Collins, Waltham, Mass.). The patients pedaled the bicycle at a constant rate beginning with a workload of 150 kpm and increasing by 150 kpm every 3 minutes. Blood pressure (cuff) and a 12-lead ECG was recorded at 2.5 minutes into each workload. The test was terminated if any of the following end points was achieved: (1) exhaustion, (2) typical angina pectoris with 24 mm horizontal ST segmentdepressionat 80 msecafter the J point, and (3) any other contraindication to continuing stress(e.g., onset of ventricular tachycardia, hypotension, left bundle branch block). A positive ECG response to stresswas defined as ~1 mm horizontal ST segment depressionat 80 msecafter the J point. Acquisition and analysis of thallium images. One minute prior to discontinuing stress the patient was injected intravenously with 2.0 mCi of thallium-201. Exercise was continued for an additional minute, after which the patient was positioned in front of a gamma camera (Ohio Nuclear, Series420) located in the sameroom asthe bicycle ergometer. The camera was equipped with a general all-purpose collimator and was interfaced to a Medical Data Systems computer system (MDS, Ann Arbor, Mich.). Imageswere obtained for 300K counts in a 128 X 128matrix in the anterior and 45-degreeleft anterior oblique projections beginning at 7 minutes and 2 hours after tracer administration. Acquisition time for each scan was carefully noted. Images were processed by one observer who was unaware of either exercise or angiographic data for the patient. The following procedure wasemployed. First, the
Volume Number
106 4. Part 1
Myocardial
128 x 128imageswere zoomed into a 64 x 64 word matrix encompassingonly the myocardium and the region immediately surrounding it. Next, a commercially available 9 point smoothing algorithm was used to smooth the zoomed images. After this the image was background corrected by means of a modified bilinear interpolative technique previously described by others.4The computer then located the pixel with maximal myocardial counts along radii drawn at each 6 degreesof arc from the center of the image (Fig. 1). Each pixel so identified was flagged by the computer and wasverified by the operator to insure that only pixels within the myocardium were analyzed. The computer then generated an uptake curve for each image. The curve consistedof the actual count values for each of the identified pixels with maximal myocardial uptake at each 6 degreesof arc. To determine if an initial uptake defect was present, each point on the curve was normalized to the point with maximal counts. The uptake curve wasthen compared againsta template derived from 14 normal patients. A defect was said to occur if two or more adjacent radii had normalized uptake values more than 2 standard deviations below the mean for normals (Fig. 1). In order to determine thallium washout at each radial location within the myocardium, uptake curves for initial and late imageswere divided by the appropriate acquisition time for each scan. The count rate at each radial location of the late (i.e., 2 hour) curve wasthen subtracted from the count rate of the corresponding point on the early curve, the result wasdivided by the count rate value for each point along the early curve and was then multiplied by 100 in order to obtain percent washout at each radial location. The resulting percent washout curve for anterior and left anterior oblique (LAO) views was compared against appropriate washout templates derived from the previously mentioned 14 normal patients. If two or more adjacent radii were more than 2 standard deviations below the mean for normal patients, delayed thallium washoutwassaid to be present. It should be noted that the method usedto assessuptake and washout abnormalities is essentially the sameas that described by Maddahi et a1.2 The intra- and interobserver variability of this method for analyzing the thallium imageswasassessed in a subset of 11 patients chosen at random from the larger study population. Intraobserver variability wasassessed by having one observer processall imagesa secondtime approximately 4 months after initial processinghad been completed. The results of uptake and washout analysis were compared on a segment-by-segmentbasis.Interobserver variability wasassessed by comparing the resultsobtained for uptake and washout analysis in 11 patients by 2 independent observers. For the purposesof assessing the presenceor absenceof triple-vessel coronary artery disease, defects of either uptake or washout along the anterior wall and septum were assignedto the left anterior descending coronary artery. Defects involving the inferior wall in the anterior view were assignedto the right coronary artery or left
Tl-201
washout
rate and triple-vessel
CAD
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circumflex if the left circumflex was a dominant system. Defects alongthe posterolateral wall in the LAO view were assignedto the circumflex coronary artery. Apical defects in the LAO view were not considered specific for any coronary vessel. Defects in the apical segment of the anterior view were assignedto the coronary vesselsupplying the apex of the left ventricle. It should be noted that the apex in both anterior and LAO views was identified by the operator and arbitrarily designatedaszero degrees.Radii were numbered proceeding counterclockwise from the apex. Accordingly, in the anterior view (Fig. 1) the apical segment extended between336 and 30 degrees,the anterior segmentextended from 36 to 130 degrees, and the inferior segment extended from 240 to 330 degrees.In the LAO view the apex extended between 336and 24 degrees,the posterolatera1segment extended between 30 and 126 degrees,and the septum extended from 246 to 330 degrees. Statistics. Sensitivity for detection of triple-vessel coronary diseasewas defined as the number of true positive tests divided by true positive plus false negative tests. Specificity was defined as true negative tests divided by true negative plus false positive tests. For the purposesof this study a true negative test was defined as a test in which a patient without triple-vessel diseasewasclassified as belonging to any category other than triple-vessel coronary artery disease.A true positive test wasdefined as a test in which a patient with triple-vessel coronary artery diseasewasassignedto the triple-vessel category. In order to evaluate the post test predictive value of thallium imaging for detecting patients with triple-vessel coronary disease,Baysian analysis of the data also wasperformed.5 Finally, it should be noted that specificity of the imaging test was evaluated in patients with normal coronary arteries by testing each patient’s uptake and washout curves against an appropriate normal template derived from the other 13 patients. This “jacknife” procedure permitted us to assessspecificity in normal patients without having to assemblea second group of normal individuals for testing against the original normal templates. RESULTS Exercise stress testing. In the triple-vessel disease group (n = 21 patients), 10 patients experienced typical angina pectoris during the test. ST segment depression greater than 1 mm was observed in 13 patients. The mean duration of exercise was 602 + 213 (SD) seconds. Mean rate-pressure product (heart rate X systolic arterial pressure) at peak stress was 19,005 r+ 6057 mm Hg . min-‘. Four patients obtained target heart rate. In the patients with single- or double-vessel coronary disease (n = 25 patients), 11 experienced typical angina pectoris during the test. Fourteen exhibited ST segment depression greater than 1 mm. Mean exercise duration in this group was 641 it 207 seconds.
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2. Shown here are the results of Baysian analysis of the imaging data. The curve depicted by closed circles (0) describes the post test probability of triple-vessel coronary artery disease (CAD) as a function of prevalence of triple-vessel CAD in a given population given a positive imaging test. The curve depicted by open circles ( 0) shows the post test probability of CAD given a negative imaging test. The difference between the two curves is shown by the triangles. The maxima of the difference function
Fig.
defines the diseaseprevalence (i.e., 40%)
at which the
imaging test best separates triple-vessel CAD patients from all other groups. The thin broken line is the line of identity. .
Mean rate-pressure product at peak stress was 19,844 +- 5394 mm Hg . min-‘. Only three patients obtained target heart rate in this group. Imaging results. In the group of patients with triple-vessel coronary artery disease, 30 of 63 vessels (48%) were associated with scan segments having both uptake and washout abnormalities. An additional 12 of 63 (19% ) diseased vessels were associated with isolated uptake defects on the thallium scan, while only 8 of 63 (13 % ) were associated with an isolated washout abnormality. Thus a relatively small percentage of all stenosed vessels were detected by delayed thallium washout alone. Nevertheless, use of combined uptake and washout criteria permitted 50 of 63 (79%) stenosed vessels to be detected. Analysis of the data on a patient-by-patient basis in the triple-vessel disease group demonstrated that 7 of 21 patients (33%) were correctly classified as having triple-vessel disease based on the presence of uptake abnormalities alone. The use of washout criteria enabled three additional patients to be recognized as having triple-vessel disease and
1983
Heart Journal
increased the percentage of patients correctly classified to 48%. In order to assess the specificity of quantitative computer analysis of thallium images for the detection of patients with triple-vessel coronary disease, we evaluated this methodology in the group of patients with single- or double-vessel coronary artery disease and in the group with angiographically normal coronary arteries. Eighty percent of patients with single- or double-vessel disease were true negative based on uptake criteria alone, while 100% of the normal patients were appropriately classified as true negative. When washout criteria were used in conjunction with uptake criteria, the percent of patients classified as true negative for triple-vessel disease declined slightly in each group: to 76% in the single- or double-vessel group and to 95% in the normal group. Accordingly, the data indicate that addition of washout to uptake criteria does not substantially reduce the specificity of the test for the diagnosis of triple-vessel coronary artery disease. Fig. 2 illustrates the results of Baysian analysis of the data. The specificity of the imaging test was found to be 76% in patients with single/doublevessel disease and 95% in normals. Since 25 of 39 (64 % ) patients without triple-vessel disease had single- or double-vessel coronary artery disease, a weighted mean value of 80% was taken as the best estimate of the true specificity of the imaging test. The sensitivity of the test was observed to be 48% but was rounded off to 50% for ease of analysis. The figure shows the post test probability of triple-vessel coronary disease as a function of the prevalence of triple-vessel disease in a given population. The curve described by the solid circles illustrates the post test probability of triple-vessel disease given a positive imaging test, while the curve described by the open circles indicates the post test probability of triple-vessel disease given a negative imaging test. The triangles represent the difference between the two curves. The point at which the difference function reaches a maximum (i.e., 40%) indicates the disease prevalence at which the test best separates patients with triple-vessel disease from all other
groups. It is apparent from the graph that with disease prevalence in the range of 30% to 50%) a negative test reduces the post test likelihood of triple-vessel disease only modestly. However, a positive test increases the post test probability of disease at least moderately (i.e., from 40% to 63%). Finally, the interobserver agreement for recogni-
Volume Number
106 4, Part 1
Myocardial
tion of scan segments with abnormal uptake was 77 % (51 of 66 scan segments), while the interobserver agreement for recognition of scan segments with abnormal washout was 80% (53 of 66 scan segments). Intraobserver agreement was found to be 79% (52 of 66 scan segments) for recognition of scan segments with abnormal uptake and 80% for recognition of scan segments with abnormal thallium washout. DISCUSSION
The principal objective of this study was to determine if quantitative computer analysis of myocardial thallium washout rates would be helpful in improving the ability of the thallium stress test to detect patients with triple-vessel coronary artery disease. In light of recent data6*7 which indicate that such patients not only achieve improved symptomatic relief but also may live longer as a result of coronary artery bypass surgery, a noninvasive method for recognition of patients with triple-vessel coronary disease would be of considerable value. Although previous investigators2g3 have emphasized that quantitative computer analysis of thallium scans, including analysis of segmental thallium washout rates, increases the recognition of diseased coronary arteries and improves the recognition of patients with multivessel coronary disease, it has not been shown that such methods of image analysis are useful in specifically recognizing the patient with triple-vessel coronary artery disease. Accordingly, the present investigation was undertaken in order to test the hypothesis that use of washout in addition to uptake criteria for recognition of defects in thallium images of the myocardium would aid in the noninvasive detection of patients with triple-vessel coronary artery disease. Improved sensitivity. The results of this investigation demonstrate that estimation of myocardial thallium washout rates does increase the sensitivity of the imaging test for recognition of patients with triple-vessel coronary artery disease. Further, although the gain in sensitivity is moderate, specificity is reduced very little by use of washout criteria. Therefore in light of the potential importance of recognizing patients with triple-vessel coronary disease, it would appear worthwhile to determine thallium washout rates in all patients undergoing thallium stress testing. Although a negative imaging test for triple-vessel disease does not exclude the diagnosis, a positive test enhances the post test probability that triple-vessel disease is present in a given patient.
Tl-201
washout
rate and triple-vessel
CAD
685
The reasons why the thallium stress test was not more sensitive in recognizing triple-vessel disease in patients is probably related to several factors. First, it must be recalled that thallium imaging provides physiologic information concerning myocardial perfusion and cell viability. In contrast, the coronary arteriogram provides anatomic information about the coronary circulation. Accordingly, because a vessel’s luminal diameter has been reduced 50% or more than 50% does not necessarily mean that it will cause myocardial ischemia during a stress test. Other more severely stenosed vessels may cause the patient to experience angina and/or even transient heart failure and so may limit the patient’s ability to exercise before other less severely stenosed vessels can cause myocardial ischemia. Second, we (present study) as well as others2s8 have observed that the range of myocardial thallium uptake and washout in normal patients is a fairly broad one. Accordingly, some marginally but abnormally perfused myocardial segments may show uptake or washout which nevertheless falls within 2 standard deviations of the mean of normals. Third, it must be recalled that the planar thallium image is a two-dimensional representation of a three-dimensional object. Accordingly, scan segments are not always seen in isolation and therefore overlap of normal and abnormal segments may in some cases prevent recognition of either uptake or washout abnormalities. Fourth, it has also been proposed by others9 that evaluation of the ST segment response to stress may, in conjunction with the results of thallium imaging, improve recognition of patients with triple-vessel disease. However, in our study all six patients with a markedly positive stress test (defined as L to 3 mm horizontal ST segment depression at a workload of 1450 kpm [equivalent to stage I of a standard Bruce protocol]) and triple-vessel coronary disease were correctly classified as true positive on the basis of thallium imaging alone. Thus addition of the ECG response to stress would not have improved the recognition of triple-vessel disease in our patients. Finally, it should be pointed out that the rate of detection of stenosed vessels in our patients with triple-vessel disease (‘79 % ) was comparable to the rate (83 % ) achieved by Maddahi et al2 in their patients with triple-vessel disease. Propranotol. The role of propranolol in influencing the results of the study should also be considered. It has been proposed that propranolol may contribute to false positive imaging tests by blunting the patient’s exercise response to stress, hence causing delayed thallium washout in normal myocardial
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segment. However, in our study specificity was high (76% in one- and two-vessel patients and 95% in normal patients). Moreover, others have shown that presence of propranolol generally does not cause false positive imaging tests as assessed by thallium washout criteria.2s3 We also observed in the triplevessel disease group that 6 of 11 patients with true positive imaging tests were taking propranolol, in comparison with 5 of 10 patients with false negative tests. Hence propranolol also did not appear to influence the results in terms of altering the incidence of true positive or false negative tests in the triple-vessel disease group. Conclusion. A computer based method for assessing washout of thallium from the myocardium offers an increase in sensitivity for detection of patients with triple-vessel coronary artery disease in comparison with assessment of initial perfusion defects alone. Given an incidence of triple-vessel disease of roughly 30% to 40% in a population, computer analysis of images using combined uptake and washout criteria is capable of increasing the post test probability of triple-vessel disease from 30% to 40 % to a range of 60% to 65%. Thus in view of the relative ease of analysis and potential importance in recognizing such patients (particularly in light of recent studies which indicate that these individuals may benefit from coronary artery bypass surgery), it is worthwhile to assess thallium washout rates in patients undergoing thallium stress testing.
American
Heart
1983 Journal
The authors express their appreciation to Christine Abatiello and Katherine Seropian for help in the preparation of the manuscript. REFERENCES
1. Beller GA, Watson DD, Ackell P, Pohost GM: Time course of thallium-201 redistribution after transient myocardial ischemia. Circulation 61:791, 1980. 2. Maddahi J, Garcia EV, Berman DS, Waxman A, Swan HJC, Forrester J: Improved noninvasive assessment of coronary artery disease by quantitative analysis of regional stress myocardial distribution and washout of thallium-201. Circulation 64:924, 1981. 3. Berger BC, Watson DD, Taylor GJ, Craddock GB, Martin RP, Teates CD, Beller GA: Quantitative thallium-201 exercise scintigraphy for detection of coronary artery disease. J Nucl Med 22:585, 1981. 4. Watson DD, Campbell NP, Reak EK, Gibson RS, Teates CD, Beller GA: Spatial and temporal quantitation of plane thallium myocardial images. J Nucl Med 22:577, 1981. 5. Hamilton GW, Trobaugh GB, Ritchie JL, Gould KL, DeRoven TA, Williams DL: Myocardial imaging with thallium-201: An analysis of clinical usefulness based on Bayes’ theorem. Scemin Nucl Med 6:358, 1978. SH: Coronary bypass surgery for chronic angi6. Rahimtoola na-1981. A perspective. Circulation 66225, 1982. 7. European Coronary Surgery Study Group: Coronary artery bypass surgery in stable angina pectoris: Survival at two years. Lancet 1:889, 1979. 8. Becker LC, Rogers WJ, Edwards AC: Limitations of thallium “washout rate” measurements after exercise for detection of coronary artery stenosis (abstr). Circulation 62(suppl III):III231, 1981. J, Barbour D, Garcia EV, Swan HJC, 9. Abdulla A, Maddahu Berman DS: Noninvasive identification of left main and triple vessel coronary artery disease in patients with prior myocardial infarction (abstr). Circulation 64(suppl IV):IV184, 1981.